With age humans become more susceptible to a number of non-infectious diseases including cancer, heart disease, type II diabetes, and neurodegenerative disorders. Insight into the mechanisms of aging will provide the foundation for the development of therapies to target the underlying factors contributing to aging. This knowledge had the potential to provide a unique opportunity to target a broad range of age related diseases with a single mechanistic intervention. An important regulator of the aging process is thought to be the mitochondrion, and many age-related diseases are associated with mitochondrial dysfunction. The long- term goal of the proposed research is to understand the joint mitochondrial and nuclear interactions that regulate aging. The Rand lab has generated novel Drosophila strains that contain mitochondrial replacements from different strains and species. Introduction of foreign mitochondria into a cell should disrupt normal mito- nuclear interactions resulting in incompatibility between mitochondrial and nuclear encoded subunits of jointly encoded enzyme complexes vital for energy production. These strains can be used as tools to dissect the mito-nuclear interactions in aging. The objective of this proposal is to examine the role of mito-nuclear interactions in dietary restriction (DR) and a genetic pathway related to DR;the Rpd3 pathway. DR is the most robust nongenetic intervention known to extend lifespan in multiple species, and in Drosophila the histone deacetylase, Rpd3, has been shown to be involved in the DR response. It is predicted the joint that mito-nuclear interactions will modulate longevity, oxidative damage, and the longevity extending effects of DR. Preliminary data in the laboratory suggests that mitochondria are involved in the DR response, and we hypothesize that mitochondria are modulating this response through the production of reactive oxygen species (ROS). This hypothesis will be tested based on the following aims: 1) determine the interaction between Rpd3 and mitochondria in longevity 2) determine if modulation of mitochondrial function and altered oxidative damage are responsible for the lifespan extension seen in the DR response to longevity. Unraveling the role of mito-nuclear cross talk in DR and the related Rpd3 pathway will provide insight into the mechanisms that regulate longevity and will clarify the role of mitochondria in longevity regulation. Understanding the underlying mechanisms of aging and DR may translate into interventions that can improve healthspan in humans. PUBLIC HEALTH RELEVANCE: With age humans become more susceptible to a number of non-infectious diseases including cancer, heart disease, type II diabetes, and neurodegenerative disorders. There is great potential in aging research as it offers the possibility of developing a single therapy to treat a broad range of age related diseases by targeting the underlying mechanisms of aging. An improvement in human health span through genetic or pharmacological interventions could enhance the quality of life for many individuals, and understanding the mechanisms of aging is vital to this process.